Pathways:
IFN-gamma pathway
Host Molecules Involved:
Protease-activated receptor-2 (PAR(2)), associated with inflammation at mucosal surfaces.
Tissues:
Respiratory tract, mucosal surfaces, bronchoalveolar lavages
Systems:
Lungs, immune system
Interactions:
PAR(2) enhances IFN- gamma production.
Mechanisms:
- In vitro, PAR(2) inhibits influenza virus type A (IAV) replication through the production of IFN-gamma.
- In vivo, PAR(2) protects mice from IAV-induced acute lung injury and death.
- This effect is associated with an enhanced clearance of IAV in the lungs, enhanced IFN- gamma production, a reduced number of neutrophils and RANTES release in bronchoalveolar fluids.
- PAR(2)-deficient mice were more susceptible to influenza infection, with more severe lung inflammation, increased neutrophil counts and RANTES concentration, and reduced IFN- gamma levels.
Effects:
During IAV infection, PAR(2) protects the host through increased IFN-gamma production and reduced excessive accumulation of inflammatory cells to lung alveoli.
Reference:
Khoufache, K., LeBouder, F., et al. (2009) Protective role for protease-activated receptor-2 against influenza virus pathogenesis via an IFN-gamma-dependent pathway. J Immunol 182, 7795-7802.
Pathways:
Toll-like receptor (TLR) signaling pathways
Host Molecules Involved:
TLR-3 is involved in antiviral and inflammatory responses of the innate immunity in response to influenza infections.
Other Molecules:
- Poly ICLC, a synthetic double stranded RNA, polyriboinosinic-poly ribocytidylic acid (Poly IC) stabilized with l-lysine (L) and carboxymethylcellulose (C).
- Poly ICLC and liposome-encapsulated Poly ICLC (LE Poly ICLC) are TLR-3 agonists, potent inducer of interferons and natural killer cells.
Tissues:
Myeloid dendritic cells, respiratory epithelium, and macrophages
Systems:
Host innate immune system
Interactions:
Nucleic acid-based agonists activate toll-like receptor (TLR) signaling pathways.
Mechanisms:
- Influenza viruses inhibit the production of interferons and the immune system’s antiviral mechanisms.
- Poly ICLC and LE Poly ICLC upregulate TLR-3 mRNAs gene expression.
- Pre-treatment of mice with Poly ICLC and LE Poly ICLC protects against highly lethal and seasonal H5N1, H1N1, and H3N2 influenza strains: A/H5N1/chicken/Henan clade 2, A/PR/8/34 [H1N1], and A/Aichi/2 [H3N2].
- Pre-treatment with CpG oligonucleotides (TLR-9 agonist) protects against influenza A/PR/8/34 infection in mice.
- The duration of protective antiviral immunity is up to 3 weeks in mice for LE Poly ICLC, 2 weeks for Poly ICLC.
Effects:
TLR-3 and TLR-9 agonists such as Poly ICLC and LE Poly ICLC may protect against lethal seasonal influenza virus infections.
Reference:
Wong, J. P., Christopher, M. E., et al. (2009) Activation of toll-like receptor signaling pathway for protection against influenza virus infection. Vaccine 27, 3481-3483.
Pathways:
The complement pathway
Influenza Molecules Involved:
The matrix (M1) protein of influenza A virus regulates the viral life cycle.
Host Molecules Involved:
Complement C1qA
Tissues:
Lung
Systems:
Host innate immune system
Interactions:
M1 interacts with complement C1qA, inhibits the classical complement pathway.
Mechanisms:
- The N-terminal domain of M1 protein is needed for binding to the globular region of C1qA.
- M1 blocks the interaction between C1qA and heat-aggregated IgG, inhibiting haemolysis.
- M1 stops the complement-mediated neutralization of influenza virus in vitro.
- M1 induces a higher virus propagation rate in the lung, reduces the survival time of mice infected with the virus.
Effects:
M1 protein is important in protecting influenza virus from the host innate immune system.
Reference:
Zhang, J., Li, G., et al. (2009) Influenza A virus M1 blocks the classical complement pathway through interacting with C1qA. J Gen Virol 90, 2751-2758.
